Nowadays, vancomycin is mostly utilized to cure gram-positive bacteria that are resistant to drugs. However, its clinical application is restricted because high-dose usage is related to nephrotoxicity. The potential efficacy of quercetin on vancomycin-induced renal damage is yet unknown. The objective of the current research was to assess the potential impacts and underlying mechanisms of quercetin against vancomycin-induced renal damage. Four groups of thirty-two male rats were created: Control (C), Quercetin (Q), Vancomycin (V), and V+Q. For seven days, groups V and V+Q were given 200 mg/kg vancomycin intraperitoneally twice daily, while Q and V+Q groups were given 100 mg/kg quercetin orally. Kidney tissues were collected for biochemical, pathological, and molecular investigation after the rats were put to death under the proper circumstances at the end of the experiment. Quercetin treatment (V+Q group) attenuated vancomycin-induced oxidative stress by increasing antioxidants (SOD, CAT, GPx) and reducing elevated MDA levels. Morever, quercetin increased antioxidant activity in association with changes in the mRNA expression levels of Nrf2, Keap1, and HO1. Additionally, quercetin reversed changes in the levels of inflammatory, apoptotic, and endoplasmic reticulum stress parameters such as Bax, Bcl-2, caspase-3, GRP78, IL-10, IL-18, iNOS, MyD88, NF-kB, p53, TLR4, and TNF-α in kidney tissue. Quercetin and also led to an elevation in PPARγ levels. Additionally, concomitant quercetin treatment preserved renal function and structural integrity. Overall, quercetin is thought to offer potential protection against vancomycin-induced nephrotoxicity by activating the Nrf2/HO1 and PPARγ pathways and suppressing inflammatory, apoptotic, and endoplasmic reticulum stress responses.